Targeting cellular senescence in dermatology: senolytic and senomorphic strategies

Abstract

Cellular senescence has emerged as a central mechanism driving cutaneous aging, impaired regeneration, and numerous dermatologic pathologies. Initially evolved as a protective mechanism to prevent malignant transformation and facilitate wound repair, senescence becomes maladaptive when senescent cells persist. Senescent keratinocytes, fibroblasts, and melanocytes can secrete pro-inflammatory mediators and other factors, collectively termed the senescence-associated secretory phenotype (SASP), which may degrade extracellular matrix components, disrupt pigmentary balance, and impair barrier function. Senescent cells are resistant to conditions that cause death of non-senescent cells and are generally removed by the immune system. Persisting senescent cells can become increasingly pro-inflammatory and fibrotic, perhaps due to accumulating DNA damage within these cells. Two primary geroscience-based therapeutic paradigms (gerotherapeutics) have been proposed: senolytics, which selectively eliminate senescent cells, and senomorphics, which modulate or suppress SASP activity without inducing senescent cell death. In dermatology, these approaches are particularly relevant given skin’s accessibility, visible aging markers, and ability to serve as a translational platform for systemic gerotherapeutic interventions. Interfering with the development of senescent cells, for example by interfering with such regulators of senescent cell formation as p16, retinoblastoma protein (pRB), p53, or p21, can be detrimental due to the protective roles of transient senescence in wound healing and cancer suppression. However, senolytics, which do not prevent senescent cells from developing but rather act by clearing already formed persisting and tissue-damaging senescent cells, offer the potential to delay, prevent, alleviate, or treat aged or fibrotic skin. Because of the days to weeks for senescent cells to form fully and their inability to divide, senolytics can be administered intermittently, for example for brief intervals every 2 weeks or once a month. Senomorphics, conversely, can modulate the detrimental effects of the SASP and generally need to be administered continuously or more frequently than senolytics. Some agents are both senolytic and senomorphic. This review considers the mechanistic underpinnings of senescence in skin, the evidence for both therapeutic approaches, and the future directions for integrating senotherapeutics into regenerative and aesthetic dermatology. Advances in cutaneous biomarkers, topical delivery systems, and AI-assisted patient stratification are expected to accelerate translation into clinical practice.

Introduction

The geroscience approach seeks to target the biological hallmarks of aging, such as cellular senescence, genomic instability, mitochondrial dysfunction, and epigenetic drift in order to delay, prevent, alleviate, or treat the multiple disorders and diseases that can occur across the lifespan that are linked to these fundamental aging mechanisms, hence extending healthspan. Among the hallmarks, cellular senescence is distinct because it can be directly visualized and experimentally manipulated in the skin, positioning dermatology at the forefront of translational aging research [1, 2].

Cellular states evolve dynamically throughout lifespan and can have distinct metabolic, genomic, and functional signatures. Most cells from younger individuals have high metabolic efficiency, preserved genomic stability, and robust proliferative potential. They can maintain telomere integrity and length, mitochondrial fitness, and effective proteostasis, supported by efficient DNA repair and antioxidant defenses. In contrast, an increasing number of cells from older individuals and in some cases, younger subjects, including even children, can harbor molecular injuries, telomere damage, mitochondrial dysfunction, and epigenetic drift, leading to reduced mitotic activity, impaired intercellular communication, and progressive decline in tissue performance. The younger individuals affected include those with such conditions as diabetes and obesity, a history of being treated with radiation or many types of chemotherapy, certain acute or chronic infections or post-infectious syndromes, several autoimmune conditions, local tissue damage (e.g., excessive sun exposure of skin, degenerative neurological diseases, renal diseases), and a number of genetic diseases, among other conditions [3–6].

Dying cells can undergo irreversible loss of viability through programmed pathways such as apoptosis or autophagy-dependent cell death, or by unregulated necrosis, ultimately ensuring the removal of irreparably damaged elements from the tissue environment. Distinct from these, senescent cells enter stable cell-cycle arrest in response to DNA damage especially in telomeres, oncogenic signaling, oxidative stress, mechanical or shear stress, extracellular damage signals (e.g., exposure to cell-free DNA or protein aggregates), and pathogen-associated molecular profile factors, such as bacterial lipopolysaccharides or viral particles, among others. Beyond remaining metabolically active, senescent cells develop a senescence-associated secretory phenotype (SASP) that can be rich in pro-inflammatory mediators, proteases, growth factors, extracellular components, aggregated or misfolded proteins (e.g., amyloid), bioactive molecules such as ROS, bradykines, or prostaglandins, and non-coding nucleotides, including micro-RNA’s and cell-free mitochondrial DNA. When senescent cells accumulate and persist, their SASP can disrupt extracellular matrix structure, alter pigmentary homeostasis, fuel chronic inflammation, spread senescence to other cells both locally and at a distance, alter immune function, promote tissue remodeling, and increase tumor risk.

In essence, while non-senescent cells sustain tissue renewal, cells from older individuals or those with accelerated aging-like states generally operate with diminished efficiency. While dying cells are eliminated, senescent cells can persist in a non-dividing yet active state that critically influences cutaneous homeostasis and aging biology. Senescence can be triggered by diverse cellular stressors including telomere dysfunction, DNA double-strand breaks and other DNA mutations, oncogenic signaling, repeated replication, exposure to growth factors such as high levels of insulin, IGF-1, or growth hormone, excess mitochondrial ROS, chronic UV exposure, and many others [7]. These stressors can activate p53/p21^CIP1, p16^INK4a/Rb, and/or related pathways, halting the cell cycle and inducing the SASP. The SASP, which depends on the cell type that became senescent, the inducer of senescence, how long the cell had been senescent, and the local microenvironment, is a complex secretome that can vary considerably over time and may be rich in cytokines, chemokines, growth factors, proteases, and other factors that shape the tissue microenvironment and have systemic consequences [8].

Cellular senescence can have beneficial effects. For example, entry into senescence of cells harboring DNA damage, oncogenic mutations, or expressing oncogenes can prevent proliferation and spread of cancerous cells. Senescence can be involved in coordinating the acute phase of wound healing through inducing removal of damaged cells and extracellular matrix remodeling [9, 10]. Hence interfering with the ability of cells to enter the senescent cell fate can promote cancer development, impair tissue remodeling and repair, and have other consequences. However, persisting senescent cells that have formed but then evaded clearance by the immune system, the usual route through which senescent cells are removed, can become increasingly pro-inflammatory, tissue-damaging, and pro-fibrotic. These persisting senescent cells can spread senescence to previously non-senescent cells and also cause immune system dysfunction [11]. This leads to further senescent cell accumulation as well as metabolic imbalance, tissue damage, and multiple disorders and diseases. These consequences of persistent senescent cell accumulation can include development and spread of cancers, especially if those senescent cells harboring cancerous mutations express immune evasion signals and, with further mutations, escape senescence [5, 12, 13].

Persisting senescent cells and their increasingly inflammatory and pro-apoptotic SASP can drive “inflammaging,” a low-grade sterile inflammatory, pro-fibrotic state that accelerates tissue dysfunction and cutaneous aging changes [14]. Notably, recent findings indicate that although the visible accumulation of senescent cells becomes more prominent after the third decade of life, the physiological capacity to clear these cells begins to decline as early as the twenties in apparently healthy individuals, highlighting a much earlier shift in senescent cell dynamics than previously appreciated [15, 16].

The skin, as a continuously regenerating organ, offers an ideal model to study the consequences of senescence and to evaluate gerotherapeutics in vivo.

Senescent cells in skin: friend and foe

In a healthy skin microenvironment, senescence can be transient and beneficial. After injury, senescent fibroblasts and keratinocytes can form and secrete PDGF-AA and MMPs, aiding matrix remodeling and re-epithelialization. The immune system then clears these cells through macrophage- and NK-cell-mediated surveillance, among other immune mechanisms.

However, with time, oxidative stress, UV exposure, mitochondrial dysfunction, and other stressors can induce more cells to become senescent. These senescent cells can spread to formerly non-senescent cells and evade and overwhelm the capacity of the immune system to clear them [17]. Hence, there is a threshold effect: once senescent cells surpass a certain abundance, their numbers increase, as demonstrated in experiments in which differing loads of autologous ear fibroblast senescent cells were transplanted back into middle-aged mice [18]. Above a burden of approximately 1 such cell being transplanted for every 10,000 cells in the recipient, frailty and onset of multiple diseases occurred causing early mortality in a pattern resembling that in older non-senescent cell transplanted mice. Below that threshold burden of transplanted senescent cells, there was little effect on recipients.

Senescent cell accumulation with aging or other processes that induce cellular senescence can occur particularly in the dermal fibroblast compartment and epidermal basal layer [19]. Persistent senescent cells can release a SASP comprising IL-6, IL-8, MMP-1, and TGF-β1 among other factors, which can disrupt dermal collagen organization and elastin integrity, leading to wrinkles, laxity, and delayed wound repair [9, 12]. Senescent melanocytes contribute to pigmentary alterations by releasing paracrine factors that dysregulate melanogenesis, while persisting senescent fibroblasts foster fibrosis or keloid formation. The accumulation of senescent immune cells, such as T cells and macrophages, also impairs surveillance and contributes to immunosenescence in the skin [20–24].

Importantly, senescence is heterogeneous: different cell types express distinct SASP signatures and exhibit variable sensitivity to interventions. This complexity underscores the need for personalized senotherapy guided by molecular profiling [22].

Senolytics: clearing the pathologically senescent

Senolytics aim to restore tissue homeostasis by selectively inducing apoptosis in senescent cells through inhibition of anti-apoptotic pathways such as ephrin-dependent Src-kinases, BCL-2 family members, and agents acting on HSP-90, PI3K/AKT, or FOXO4-p53 interactions, among others.

The combination of dasatinib (an ephrin-dependent Src tyrosine kinase inhibitor) and quercetin (a flavonoid) was the first senolytic cocktail shown to eliminate senescent fibroblasts and improve tissue function in aged mice [25, 26]. In dermatologic models, senolytics have demonstrated:

• Enhanced dermal matrix regeneration and reduced collagen degradation after UV exposure

• Accelerated wound closure and improved re-epithelialization

• Reduced inflammatory burden and normalized fibroblast function

Emerging candidates such as fisetin, navitoclax (ABT-263), and a FOXO4-DRI peptide show promise, though toxicity and delivery challenges persist. For instance, navitoclax effectively clears senescent fibroblasts but can induce thrombocytopenia due to platelet BCL-xL inhibition and can cause severe, unpredictable neutropenia.

In dermatology, topical senolytics, delivered by microneedles, nanocarriers, or pH-activated hydrogels, represent an innovative approach to minimize systemic exposure. The use of prodrug systems activated by local oxidative stress could further enhance safety and specificity.

It is anticipated that if they are translated into clinical use and attain regulatory approval, senolytics will be applied intermittently and judiciously. So far, senolytics do not interfere with generation of senescent cells and in preclinical models and they do not appear to impede cancer suppression or chronic wound repair, unlike in genetic models in which senescent cell generation is interfered with. Furthermore, senolytics can be administered intermittently and most have short elimination half-lives, which may reduce off-target effects [27]. This is feasible since senolytics can kill senescent cells within 18 h after exposure, senescent cells generally cannot divide, and it can take up to several weeks for new senescent cells to reaccumulate. Furthermore, senolytics only target the 30 to 70% of senescent cells that are pro-apoptotic, not those that release a predominantly pro-growth SASP. This is unlike certain genetic mouse models from which senescent cells and other cell types, including activated macrophages, with high expression of p16/p19 can be selectively eliminated. In the latter genetic models, skin wound healing can be interfered with, unlike what appears to be the case with senolytics.

Senomorphics: modulating the SASP

Senomorphics, or senostatics, suppress the pro-inflammatory SASP without directly eliminating senescent cells. This approach can allow preservation of beneficial paracrine signaling while reducing tissue-damaging inflammation [28–30].

• Rapamycin, an mTOR inhibitor, downregulates SASP transcription through mTORC1 suppression and enhances autophagy. A small clinical study showed topical rapamycin reduced p16^INK4a expression and visibly improved skin texture in elderly volunteers [31].

• Metformin acts through AMPK activation and NF-κB inhibition, reducing oxidative stress and systemic inflammation. Topical metformin formulations are being tested for photoaging and diabetic ulcers [32].

• JAK inhibitors block SASP-mediated cytokine signaling and are already used in inflammatory dermatoses, potentially serving as indirect senomorphics [33].

• Flavonoids such as apigenin and kaempferol exhibit multi-target SASP modulation, particularly through the MAPK/NF-κB pathways [34].

Senomorphics are well suited for chronic management of inflammation and pigmentation disorders but may require continuous use. Their long-term effects on immune surveillance, the skin microbiome, and other potential local and systemic adverse effects remain to be fully explored.

Senolytics vs. senomorphics: complementary or competing?

Rather than competing, these two strategies can be viewed as sequential or combinatorial tools to manage cutaneous senescence. Senolytics offer periodic clearance of heavily senescent populations, while senomorphics provide ongoing modulation of the SASP to prevent recurrence (Table 1). Since senomorphics interfere with the pro-apoptotic SASP, they can interfere with senolytics, which act by disabling mechanisms that the 30 to 70% of pro-apoptotic senescent cells use to protect themselves against their own SASP. This potential issue might be circumvented by sequencing senolytics and senomorphics so they are not administered at the same time.

Table 1.

Senolytic and senomorphic agents with dermatological relevance

Category	Representative agents	Mechanism of action	Dermatologic applications (preclinical/clinical)	Possible clinical benefits
Senolytics	Dasatinib + quercetin	Inhibits tyrosine kinases (including ephrin-dependent Src kinase) and PI3K; induces apoptosis in senescent fibroblasts	Improves dermal matrix in UV-induced photoaging	Improved firmness, smoother texture, reduced fine lines
	Fisetin	Flavonoid; modulates BCL-2 and oxidative pathways among others	Antioxidant and anti-photoaging effects in mice	Enhanced luminosity and reduced erythema in preclinical models
	Navitoclax (ABT-263)	BCL-2/BCL-xL inhibition	Anti-fibrotic in preclinical skin models	Reduced dermal stiffness; normalization of tissue tone
	FOXO4-DRI peptide	Disrupts FOXO4–p53 interaction to trigger apoptosis	Promotes clearance of senescent keratinocytes	Improved epidermal renewal; potential reduction in hyperpigmented areas
Senomorphics	Rapamycin	mTOR inhibition; partial SASP suppression	Reduces p16INK4a and improves skin quality in elderly volunteers	Smoother texture, decreased roughness, improved elasticity
	Metformin	AMPK activation; NF-κB inhibition	Reduces oxidative stress; emerging topical interest	Reduction in erythema and dullness; enhanced glow
	Ruxolitinib	JAK-STAT inhibition	SASP modulation in inflammatory dermatoses	Reduction in chronic redness and irritation
	Apigenin, kaempferol	Flavonoids; NF-κB and MAPK suppression	Anti-inflammatory and anti-pigmentary potential	Improved evenness of tone, decreased dullness

Emerging frontiers in cutaneous geroscience

Epigenetic and mitochondrial targets

Senescence is intertwined with epigenetic drift, global DNA hypomethylation, and histone modification changes that alter chromatin accessibility. Modulating epigenetic regulators such as sirtuins (SIRT1, SIRT3) and histone deacetylases (HDACs) offers a promising avenue to delay or reverse these aging-associated changes. Among emerging interventions, NAD⁺precursors and resveratrol analogs have demonstrated senomorphic potential by reinforcing mitochondrial performance and maintaining epigenetic homeostasis [35]. Recent insights further underscore the central role of NAD⁺metabolism as a biological bridge between systemic metabolic health and cutaneous health, enhancing redox balance, cellular energy renewal, and the regenerative capacity of aging skin cells [36].

The skin–systemic axis

Cutaneous senescence contributes to systemic inflammation through SASP diffusion into circulation. Conversely, systemic senotherapies may rejuvenate skin indirectly, positioning the skin as a sentinel organ for monitoring systemic aging interventions [37]. The skin should therefore be viewed not only as a visible marker of aging, but also as a dynamic functional organ whose progressive senescence may contribute to frailty, impaired resilience, and declining healthspan.

Skin function, dermatoporosis, and the skin–systemic health axis

Beyond its value as a visible and accessible readout of biological aging, the skin should be considered a functional organ whose age-related decline may influence overall healthspan. Aging skin undergoes progressive impairment of barrier integrity, immune surveillance, neuroendocrine signaling, thermoregulation, sensory perception, wound repair, and extracellular matrix resilience [38]. Senescence-associated alterations in keratinocyte turnover and epidermal lipid organization may further impair barrier homeostasis, increasing transepidermal water loss (TEWL), susceptibility to infection, chronic inflammation, and delayed repair. Cutaneous immunosenescence further contributes to impaired antimicrobial defense, altered inflammatory responses, reduced vaccine responsiveness, and delayed tissue recovery in aging skin. Beyond structural integrity, the skin also functions as a neuroendocrine interface capable of producing hormones, neuropeptides, and cytokines that participate in systemic homeostasis and stress responses. These changes are not merely cosmetic; they contribute to increased susceptibility to infection, delayed healing, chronic inflammation, frailty-related complications, and reduced quality of life [39, 40].

Dermatoporosis, or chronic cutaneous insufficiency and fragility syndrome, illustrates this functional dimension of skin aging. It is characterized by dermal atrophy, senile purpura, pseudoscars, skin tears, impaired repair capacity, and in advanced cases deep dissecting hematomas. Importantly, dermatoporosis shares biological and clinical features with systemic aging disorders, particularly osteoporosis and frailty. Reported associations between skin fragility, reduced dermal thickness, impaired extracellular matrix integrity, and bone health suggest that the skin may reflect broader connective tissue and musculoskeletal aging. Emerging evidence further suggests that skin fragility and dermatoporosis may serve as clinically accessible biomarkers of systemic frailty and biological aging. Therefore, interventions capable of restoring cutaneous structure and function may have implications beyond appearance, potentially contributing to improved resilience, mobility, wound outcomes, and overall geroscience-oriented health [41–43].

In this context, senolytic and senomorphic strategies should not be viewed solely as aesthetic rejuvenation tools. By reducing the burden or inflammatory activity of senescent keratinocytes, fibroblasts, melanocytes, endothelial cells, and immune cells, senotherapeutics may help restore barrier competence, improve dermal matrix organization, enhance wound repair, and modulate local immune and neuroendocrine signaling. Future studies should therefore include functional endpoints such as TEWL, skin thickness, biomechanical properties, wound healing capacity, skin tear risk, inflammatory biomarkers, microbiome resilience, and validated dermatoporosis scores. Such endpoints would better align cutaneous senotherapeutics with the broader goals of geroscience: preserving organ function, reducing frailty-related morbidity, and extending healthspan (Table 2).

Table 2.

Functional consequences of cutaneous senescence

Functional domain	Age-related consequence
Barrier function	Increased TEWL, xerosis, infection susceptibility
Immune function	Immunosenescence, impaired antimicrobial defense
Repair capacity	Delayed wound healing
Mechanical integrity	Dermatoporosis, skin tears, fragility
Neuroendocrine signaling	Altered stress-response communication
Systemic implications	Frailty and osteoporosis correlations

Combination and adaptive senotherapies

Future protocols may combine intermittent senolytics for cellular clearance with cycles of senomorphics for maintenance, guided by real-time biomarker feedback. Integration with exosome-based rejuvenation therapies, antioxidant peptides, or energy-based devices (e.g., lasers inducing regenerative senescence in a controlled manner) could further enhance outcomes [44]. Looking ahead, consensus on standardized terminology in the field of cellular senescence, particularly regarding the classification of senolytic and senomorphic mechanisms, SASP components, and biomarker definitions, will be instrumental in fostering interdisciplinary communication, regulatory clarity, and global integration of senotherapeutic research within dermatology [45].

Artificial intelligence and predictive dermatology

Artificial intelligence (AI) is rapidly transforming dermatologic research by enabling the high-dimensional integration of molecular, imaging, and clinical data. Deep learning algorithms can now detect subtle phenotypic signatures of cellular senescence, including textural changes, pigmentation heterogeneity, or vascular micro-patterns, on dermoscopic, reflectance confocal, and optical coherence tomography (OCT) images, often surpassing human diagnostic sensitivity. Machine learning–based image classifiers trained on senescent cell morphologies and autofluorescence features have shown potential to distinguish chronologically aged from photoaged skin and to detect subtle inflammatory or structural alterations before overt clinical manifestations. Emerging studies suggest that some computational imaging features may correlate with senescence-associated biomarkers, including p16^INK4a, p21^CIP1, and SASP-related inflammatory signatures, although these associations remain preliminary and require further validation in larger translational and clinical studies [4, 30].

Beyond diagnosis, predictive modeling and digital twins, virtual, data-driven replicas of individual skin systems that simulate biological behavior, are emerging tools that simulate cutaneous aging trajectories and therapeutic outcomes. By combining data from genomics, transcriptomics, metabolomics, and the skin microbiome, AI-driven algorithms can construct individualized “skin age clocks,” analogous to epigenetic clocks used in systemic aging research [30, 46]. These models may soon allow clinicians to quantify responses after senolytic or senomorphic treatments or predict treatment responses based on cellular senescence burden and characteristics.

Furthermore, multi-modal AI integration, linking 3D imaging, spectroscopy, and molecular profiling, can support precision senotherapy. For instance, unsupervised clustering of skin transcriptomes could identify patients whose senescence profile guides specific therapeutic strategies. Coupled with AI-optimized topical formulations and real-time feedback from smart wearables monitoring microcirculation, oxidative stress, or barrier function, the next frontier of predictive dermatology will move toward closed-loop rejuvenation systems capable of autonomous, adaptive treatment modulation [30, 47].

Finally, federated learning approaches are being proposed to ensure data privacy and algorithmic generalizability across diverse skin types, a critical step for fair and inclusive dermatologic AI. Integration of these models within clinical devices could redefine not only aesthetic outcomes, but also biological skin resilience and healthspan assessment.

Ethical and regulatory implications

As senotherapeutics transition from experimental models to aesthetic and regenerative dermatology, ethical and regulatory frameworks must evolve to address the novel challenges they pose. The boundary between medical intervention and cosmetic enhancement becomes increasingly blurred when therapies aim not merely to reverse visible aging changes but to modify biological aging mechanisms. Regulatory agencies such as the FDA and EMA currently classify senolytics and senomorphics based on therapeutic intent rather than molecular targets, but their use for rejuvenation raises critical questions about risk-benefit balance, long-term safety, and public access [44, 48].

Ethical considerations include the potential medicalization of aging, whereby normal physiological processes are pathologized, and the inequity of access to expensive or proprietary anti-senescence therapies. If senotherapeutics extend beyond aesthetic benefit to confer healthspan advantages, access could become a public health issue, not merely a luxury service. Transparent communication about realistic expectations, biological variability, and potential off-target effects, such as impaired wound healing or immune modulation, is essential to maintain public trust.

Another concern involves AI governance and bias. Predictive dermatology algorithms trained primarily on lighter skin phototypes risk reinforcing existing disparities in diagnosis and treatment outcomes. Ensuring algorithmic transparency, explainability, and cross-ethnic validation is imperative for ethical deployment. Similarly, the storage and use of sensitive biometric and genomic data raise issues of consent and data ownership that must be regulated under frameworks like the EU’s GDPR and upcoming AI Act [49].

From a bioethical perspective, the concept of “healthspan” challenges traditional definitions of therapy. While senotherapeutics aim to restore apparently youthful cellular function, they may also reshape cultural perceptions of aging, potentially reinforcing age-related stigma and unrealistic beauty standards [50]. Academic societies and dermatologic associations should thus promote recommendations distinguishing between interventions intended for health restoration versus elective enhancement, emphasizing well-being and functionality over mere appearance [51, 52].

In the near future, regulatory bodies will likely require standardized biomarkers of senescence and validated AI-based diagnostic endpoints before approving senotherapeutic products. Collaborative efforts among clinicians, bioengineers, ethicists, and regulators are essential to ensure that advances in cutaneous geroscience are deployed safely, equitably, and responsibly, enhancing healthspan, dignity, and diversity in human aging.

Conclusions

Cellular senescence represents a cornerstone of cutaneous aging and pathology, bridging molecular geroscience with clinical dermatology. The emerging dual strategies of senolytics and senomorphics provide a rational and complementary framework for targeting this process.

Senolytics offer rejuvenation through selective clearance of dysfunctional cells, while senomorphics sustain balance by tempering inflammation. Both senolytics and senomorphics can preserve beneficial repair mechanisms; neither approach prevents development of senescent cells when needed. Combined with advancements in biomarkers, AI-guided diagnostics, and topical delivery technologies, dermatology is poised to lead the clinical translation of senotherapeutics. Accordingly, future senotherapeutic strategies in dermatology should prioritize preservation of cutaneous function, resilience, and systemic health in addition to visible rejuvenation.

Ultimately, targeting senescence is not merely about aesthetic rejuvenation, it is about restoring cellular resilience, metabolic harmony, and cutaneous health, aligning the skin with the broader goals of systemic healthspan extension.

Funding

J.L.K.: US National Institutes of Health (NIH) grants R37AG013925 and R33AG061456, Hevolution Foundation grant HF-GRO-23-1199148-3, the Connor Fund, and Robert J. and Theresa W. Ryan.

Data availability

The data supporting the findings of this study are available from the references cited within this article.

Declarations

Ethics approval

No human or animal studies were conducted; ethical approval was not applicable.

Patient consent

Not applicable.

Conflict of interest

The authors declare no competing interests.